The journal of pain : official journal of the American Pain Society
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Opiates are currently the mainstay for treatment of moderate to severe pain. However, prolonged administration of opiates has been reported to elicit hyperalgesia in animals, and examples of opiate-induced hyperalgesia have been reported in humans as well. Despite the potential clinical significance of such opiate-induced actions, the mechanisms of opiate-induced hypersensitivity remain unknown. The transient receptor potential vanilloid1 (TRPV1) receptor, a molecular sensor of noxious heat, acts as an integrator of multiple forms of noxious stimuli and plays an important role in the development of inflammation-induced hyperalgesia. Because animals treated with opiates show thermal hyperalgesia, we examined the possible role of TRPV1 receptors in the development of morphine-induced hyperalgesia using TRPV1 wild-type (WT) and knock-out (KO) mice and with administration of a TRPV1 antagonist in mice and rats. Administration of morphine by subcutaneous implantation of morphine pellets elicited both thermal and tactile hypersensitivity in TRPV1 WT mice but not in TRPV1 KO mice. Moreover, oral administration of a TRPV1 antagonist reversed both thermal and tactile hypersensitivity induced by sustained morphine administration in mice and rats. Immunohistochemical analyses indicate that sustained morphine administration modestly increases TRPV1 labeling in the dorsal root ganglia. In addition, sustained morphine increased flinching and plasma extravasation after peripheral stimulation with capsaicin, suggesting an increase in TRPV1 receptor function in the periphery in morphine-treated animals. Collectively, our data indicate that the TRPV1 receptor is an essential peripheral mechanism in expression of morphine-induced hyperalgesia. ⋯ Opioid-induced hyperalgesia possibly limits the usefulness of opioids, emphasizing the value of alternative methods of pain control. We demonstrate that TRPV1 channels play an important role in peripheral mechanisms of opioid-induced hyperalgesia. Such information may lead to the discovery of analgesics lacking such adaptations and improving treatment of chronic pain.
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Clinical Trial
Psychologic influence on experimental pain sensitivity and clinical pain intensity for patients with shoulder pain.
Pain-related fear and pain catastrophizing are 2 central psychologic factors in fear-avoidance models. Our previous studies in healthy subjects indicated that pain-related fear, but not pain catastrophizing, was associated with cold pressor pain outcomes. The current study extends previous work by investigating pain-related fear and pain catastrophizing in a group of subjects with shoulder pain, and included concurrent measures of experimental and clinical pain. Fifty nine consecutive subjects seeking operative treatment of shoulder pain were enrolled in this study (24 women, mean age = 50.4, SD = 14.9). Subjects completed validated measures of pain-related fear, pain catastrophizing, and clinical pain intensity and then underwent a cold pressor task to determine experimental pain sensitivity. Multivariate regression models used sex, age, pain-related fear, and pain catastrophizing to predict experimental pain sensitivity and clinical pain intensity. Results indicated that only pain-related fear uniquely contributed to variance in experimental pain sensitivity (beta = -.42, P < .01). In contrast, sex (beta = -.29, P = .02) and pain catastrophizing (beta = .43, P < .01) uniquely contributed to variance in clinical pain intensity. These data provide additional support for application of fear-avoidance models to subjects with shoulder pain. Our results also suggest that pain-related fear and pain catastrophizing may influence different components of the pain experience, providing preliminary support for recent theoretical conceptualizations of the role of pain catastrophizing. ⋯ This study provided additional information on how specific psychological variables potentially influence experimental and clinical pain. In this sample of subjects with shoulder pain, we replicated findings from our previous studies involving healthy subjects, as fear of pain was uniquely associated with experimental pain sensitivity. In contrast, pain catastrophizing emerged as the sole psychological variable related to clinical pain intensity.
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Previous research indicates that exposure to shock decreases thermal pain sensitivity in humans. This hypoalgesia has been attributed to a centrally mediated fear state that activates descending inhibitory pathways. Animal research suggests that distraction alters the activation of these hypoalgesic systems. To determine whether the pain memory alters the activation of hypoalgesic systems in humans, the present study examined whether a post-shock distractor attenuates shock-induced hypoalgesia. If fear-inducing shocks are represented by a limited capacity working memory system, then a distractor should speed the decay of the hypoalgesia. Healthy men were randomly assigned to 1 of 4 groups: shock-distraction, shock-no distraction, no shock-distraction, and no shock-no distraction. Following baseline pain tests, participants in the shock groups were presented with 3 brief shocks. Immediately following shock, an unexpected vibration stimulus was presented to participants in the distraction groups. Both self-report and physiological (SCL, HR) measures indicated that shock exposure resulted in fear, arousal, and decreased pain sensitivity. Consistent with prior animal studies, presentation of a post-shock distractor sped the decay of shock-induced hypoalgesia. Specifically, the distraction group exhibited significantly less shock-induced hypoalgesia compared to the no-distraction group. These findings provide additional evidence for the involvement of memory processes in the activation of descending pain inhibitory pathways. ⋯ This study demonstrated that the presentation of a distracting stimulus immediately following 3 brief shocks attenuated shock-induced hypoalgesia in healthy human subjects. Understanding the impact of post-pain distraction on pain processing may have important clinical implications because it may influence patients' willingness to undergo future painful medical procedures.
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Although intrathecal (i.t.) administration of the alpha(2)-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an alpha(2)-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects. ⋯ This study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.
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Arthritis is associated with decreases in local pH. Of the acid-sensing ion channels (ASIC), ASIC3 is most sensitive to such a pH change, abundantly expressed in dorsal root ganglion (DRG), and critical for the development of secondary hyperalgesia. The purpose of this study was to investigate the upregulation of ASIC3, using an acute arthritic pain model in mice. We examined ASIC3 expression in DRG neurons innervating the knee joint with and without carrageenan-induced arthritis by means of retrograde labeling and immunohistochemistry. We also examined the difference of DRG phenotype between ASIC3+/+ and ASIC3-/- mice. ASIC3 immunoreactivity was present in 31% of knee joint afferents and dominantly in small cells. After joint inflammation, ASIC3-immunoreactive neurons significantly increased in number by 50%. Calcitonin gene-related peptide (CGRP) increased similarly in both ASIC3+/+ and ASIC3-/- mice. Soma size distribution of ASIC3-immunoreactive neurons without CGRP expression was shifted to smaller-diameter neurons. Our results suggest that ASIC3 plays an important role in acute arthritic pain. Specifically, we propose that ASIC3 upregulation along with CGRP and phenotypic change in ASIC3-immunoreactive neurons without CGRP are responsible for the development of secondary hyperalgesia after carrageenan-induced arthritis. ⋯ This article shows that ASIC3 is upregulated along with CGRP in knee joint afferents and that there is a phenotypic change in ASIC3-immunoreactive nonpeptidergic neurons in an animal model of acute arthritis. Understanding the basic neurobiology after acute arthritis could lead to future new pharmacological management of arthritis.